Highlights from Recent Cancer Literature
Journal: Cancer Research (2011)

Schioppa T, Moore R, Thompson RG, Rosser EC, Kulbe H, Nedospasov S, et al. B regulatory cells and the tumor-promoting actions of TNF-{alpha} during squamous carcinogenesis. Proc Natl Acad Sci U S A 2011;108:10662–7.It can be argued that the inflammatory cytokine tumor necrosis factor a (TNF-α) is wrongly named. Although local delivery of this cytokine to tumors undoubtedly causes destruction of blood vessels and dramatic tissue necrosis, when it is secreted by malignant tumor cells and/or infiltrating immune cells in the cancer microenvironment, TNF also is well documented for its tumor-promoting activities. Thus, TNF is now recognized as a major mediator of cancer-related inflammation. It has been known for over a decade that TNF-deficient (-/-) mice are resistant to experimental 7,12-dimethylbenz[α]anthracene/terephthalic acid (DMBA/TPA)-induced skin carcinogenesis. Now one of the major effector cells of TNF action in this model has been identified–and the story has a surprising contemporary twist. In a recent article, Schioppa and colleagues posed the following question: Because TNF-/- mice have well-documented B-cell defects, and because B cells promote tumor formation in genetic models of skin and prostate cancer, are the tumor-promoting actions of TNF mediated by B cells? Using mice with various immune deficiencies, Schioppa and colleagues revealed that B cells were indeed tumor promoting in the DMBA/TPA skin carcinogenesis model. The hypothesis relating to TNF was confirmed when transfer of wild-type B cells to TNF-/- mice significantly restored both the penetrance and kinetics of skin papilloma development. But how did B cells regulate this development? In the absence of TNF, Schioppa and colleagues found increased skin infiltration of CD8+ T cells (generally considered antitumor), concomitant with decreased infiltration by macrophages, reflected in elevated levels of the T-cell chemokine CCL5 and the antitumor cytokine IFN-γ, indicating that, in the absence of TNF, mice mount a T-helper 1-type antitumor response and thereby limit neoplastic progression by essentially reprogramming the immune microenvironment. However, B cells do more than merely produce antibodies. They are also major regulators of immunity via cytokine production, and in particular interleukin (IL)-10. The authors postulated that IL-10- producing B cells, i.e., regulatory B cells (Breg), were in fact mediators of TNF action, and indeed, they revealed that TNF-/- mice contained significantly diminished populations of Breg cells. These results extend our understanding of the links between cancer and inflammation. During chronic inflammation, Bregs dampen potentially harmful T-lymphocyte-mediated autoimmune reactions; however, an unwanted outcome of this immune suppression may be that T cells fail to recognize and destroy cells with acquired oncogenic mutations. Thus, against a background of chronic inflammation, the actions of Bregs may allow malignant cells to surviveand proliferate.Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 2011 Jun 8. [Epub ahead of print].A recent article identifies CCL2 as a key regulator of breast cancer pulmonary metastasis. Using a mouse model of human breast cancer, Qian and colleagues revealed a critical role for the monocyte/macrophage chemokine CCL2. When breast carcinoma cells metastasize to the lung, they secrete CCL2, a chemokine for inflammatory monocytes. In turn, inflammatory monocytes are recruited to metastatic sites, attracted by CCL2, secreted not only by metastatic carcinoma cells but also by activated resident cells in the lung microenvironment. As a result, continuous recruitment of monocytes and the macrophages into which they mature promotes ongoing growth of the emerging metastatic tumor. Neutralizing anti-CCL2 antibodies suppressed CCL2 signaling and inhibited influx of inflammatory monocoytes and macrophages to metastatic sites, resulting in a significant reduction n in the number of metastatic foci in lungs of tumorbearing mice, which resulted in turn in a significant survival advantage. These findings are easily translatable to anti-breast cancer therapy because CCL2 expression and macrophage infiltration in human breast cancer are associated with poor prognosis and metastatic disease; thus, targeted therapies blocking CCL2-dependent signaling would effectively diminish metastasis and thereby provide enhanced long-term survival for these patients.Martin D, Galisteo R, Molinolo AA, Wetzker R, Hirsch E, Gutkind JS. PI3K gamma mediates Kaposi's sarcoma-associated Herpesvirus vGPCR-induced sarcomagenesis. Cancer Cell 2011;19:805–13.Schmid MC, Avraamides CJ, Dippold HC, Franco I, Foubert P, Ellies LG, et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3Kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell 2011;19:715-27.The four class I phosphoinositide-3 kinases (PI3K) phosphorylate lipid substrates, regulating a large number of cellular processes. Inhibitors that are relatively nonselective among the class I catalytic subunits are well into clinical testing, while small molecule agents specific for individual class I enzymes are just entering clinical trials. What is the preclinical and clinical utility of isoform-selective inhibitors of class I PI3Ks? PI3Kγ signals through a G-protein-coupled receptor (GPCR), with expression largely restricted to immune cells. Two recent articles provide evidence that inhibition of PI3Kγ in myeloid cells significantly regulates solid tumor development. Martin and colleagues show that inhibition of PI3Kγ blocks progression in a mouse model for Kaposi sarcoma, in which tumor cells do not express PI3Kγ. Schmid and colleagues report that PI3Kγ is an unexpected target of activation of chemoatractants that activate GPCRs, receptor tyrosine kinases (RTK), and toll-like receptors, and specifically, RTKs and interleukin-1 receptors induce inflammation by activating the PI3K isoform p110γ in myeloid cells. In turn, these myeloid cells infiltrate tumors and thereby contribute to tumor growth and metastasis; pharmacologic inhibition of p110γ suppressed growth of breast carcinoma cells in vivo. Thus, two groups of researchers have uncovered a surprising nexus showing a possible therapeutic strategy for targeting inflammation to halt tumor progression and have clarified interactions between infiltrating myeloid cells and tumor cells in malignancy. These findings support the importance of PI3Kγ as a potential therapeutic target, even in cancers that do not express this kinase.Vitari AC, Leong KG, Newton K, Yee C, O'Rourke K, Liu J, et al. COP1 is a tumor suppressor that causes degradation of ETS transcription factors. Nature 2011;474:403–6.E26 transformation-specific (ETS) family transcription factors are among the most frequent drivers of prostate cancer. Vitari and colleagues identified COP1 as an E3 ligase that regulates degradation of many ETS family members. Importantly, ETV1, which is frequently activated in prostate cancer (through translocation), typically shows loss of COP1 binding sites, leading to stabilization. Prostate-selective deletion of COP1 drove increased levels of ETV1 in vivo, and was associated with early signs of prostatic transformation. Rare human prostate cancers showed deletion of COP1, associated with increased levels of ETV1 in the absence of ETV1 translocation. These findings clarify post-translational processing of ETS family transcription factors in the prostate and identify COP1 as a tumor suppressor in prostate cancer.Mehta H, Gao Q, Galet C, Paharkova V, Wan J, Said JW, et al. IGFBP-3 is a metastasis suppression gene in prostate cancer. Cancer Res 2011:71:5154–63.The insulin-like growth factor binding protein-3 (IGFBP3) has been implicated in many aspects of tumorigenesis, including regulation of proliferation, senescence, apoptosis, and angiogenesis. Moreover, recent epidemiologic studies have hinted that loss of IGFBP3 is associated with more aggressive prostate cancer. Using a murine model of prostate carcinogenesis, Mehta and colleagues report that deletion of IGFBP3 induces a marked increase in metastasis, with 55% of mice showing lung involvement of tumor. To characterize the mechanism, the authors revealed that loss of IGFBP3 is associated with increased colony formation and growth, as well as an epithelial-to-mesenchymal phenotype of malignant cells in a Myc-driven model of prostate cancer. Hence, the investigators provide an in vivo model of metastatic prostate cancer causally regulated by IGFBP-3.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.